Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

Pierre Dagher, Takashi Hato, Henry E. Mang, Zoya Plotkin, Quentin V. Richardson, Michael Massad, Erik Mai, Sarah E. Kuehl, Paige Graham, Rakesh Kumar, Timothy Sutton

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.

Original languageEnglish (US)
JournalInternational Journal of Molecular Sciences
Volume17
Issue number5
DOIs
StatePublished - Apr 29 2016

Fingerprint

fibrosis
Toll-Like Receptor 4
kidneys
Acute Kidney Injury
Fibrosis
deletion
Macrophages
Cell death
Infiltration
renal function
Animals
mice
kidney diseases
Kidney
creatinine
neutrophils
rarefaction
animal models
macrophages
Renal Artery

Keywords

  • acute kidney injury
  • fibrosis
  • ischemia-reperfusion
  • toll-like receptor 4

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury. / Dagher, Pierre; Hato, Takashi; Mang, Henry E.; Plotkin, Zoya; Richardson, Quentin V.; Massad, Michael; Mai, Erik; Kuehl, Sarah E.; Graham, Paige; Kumar, Rakesh; Sutton, Timothy.

In: International Journal of Molecular Sciences, Vol. 17, No. 5, 29.04.2016.

Research output: Contribution to journalArticle

Dagher, Pierre ; Hato, Takashi ; Mang, Henry E. ; Plotkin, Zoya ; Richardson, Quentin V. ; Massad, Michael ; Mai, Erik ; Kuehl, Sarah E. ; Graham, Paige ; Kumar, Rakesh ; Sutton, Timothy. / Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury. In: International Journal of Molecular Sciences. 2016 ; Vol. 17, No. 5.
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